Process for n-acylating novenamine

ABSTRACT

A process for preparing N-acylated novenamine having antibacterial activity comprising contacting novenamine with an acylating agent consisting of a derivative of the desired carboxylic or sulfonic acid in a nitrogen-containing organic base at a temperature of from about -80*C. to about 0*C., and allowing the reaction system to come to ambient temperature.

D United States Patent 1 [111 3,890,297

Dolak June 17, 1975 [54] PROCESS FOR N ACYLATING 3,296,246 1/1967 Ores ct a1 260/210 AB 3,652,536 3/1972 Sebek et al NOVENAMINE 3,689,474 9/1972 Kagan et al 260/210 R [75] Inventor: Lester A. Dolak, Kalamazoo, MlCh.

[73] Assignee: The Upjohn Company, Kalamazoo, Primary Examiner-Johnnie Brown Mi Attorney, Agent, or FirmMartin B. Barancik; Roman Saliwanchik [22] Filed: Mar. 29, 1973 [2]] Appl. No.: 346,010 [57] ABSTRACT A process for preparing N-acylated novenamine hav- 52 us. Cl 260/210 R ing antibacterial activity comprising contacting 51 Int. Cl. (30% 47/18 noveiiamiiie with an acylating agent Consisting of a 58 Field of Search 260/210 R, 210 AB rivative of the desired carboxylic 0r sulfonic acid in a nitrogen-containing organic base at a temperature of [56] References Cited from about 80C. to about 0C., and allowing the re- UNITED STATES PATENTS 4/1966 Schaffner et al. 260/210 AB action system to come to ambient temperature.

4 Claims, No Drawings PROCESS FOR N-ACYLATING NOVENAMINE BRIEF DESCRIPTION OF THE PRIOR ART In U.S. Pat. No. 3,652,536, the preparation of novenamine, the portion of novobiocin which remains after cleavage of the amide bond, and novenamine N- acylates was disclosed. However, none of the acylation processes prepared the N-acylate selectively. When novenamine was acylated in aprotic solutions containing an acid binding agent, O-acylation occurred as well as N-acylation. The O-acyl group was removed by treatment with liquid ammonia, a process which is inconvenient, costly and potentially hazardous. To avoid the formation of novenamine O-acylates, the acylation reaction was alternatively carried out in a hydroxyl solvent such as water or ethanol. In this case, the solvent was also acylated and had to be separated from the N- acylated novenamine. Additionally, both of these processes suffered from the disadvantages of a tedious work-up of complex reaction mixtures and the final isolation of the N-acylated novenamine by column chromatography.

The process of this invention produces N-acylated novenamine selectively and allows rapid isolation and characterization of the N-acyl derivatives. The process is additionally advantageous in that the N-acylated products can be obtained from impure novenamine starting material as readily as from pure novenamine. The N-acylated novenamine compounds have antibacterial activity.

BRIEF SUMMARY OF THE INVENTION A process is provided for preparing N-acylated novenamine having anti-bacterial activity comprising contacting novenamine with an acylating agent consisting of a derivative of the desired carboxylic or sulfonic acid in a nitrogen-containing organic base at a temperature of from about 80C. to about C., and allowing the reaction system to come to ambient temperature.

DETAILED DESCRIPTION OF THE INVENTION Novenamine is readily prepared by the procedure of US. Pat. No. 3,652,356. Impure novenamine can be employed as readily in the instant process as further purified novenamine. Impure novenamine means a novenamine content of up to about to weight percent.

The novenamine, or its hydrochloride salt, is dissolved in a nitrogen-containing organic base with or without cosolvent. The solvent system should have the capability of solubilizing, but not necessarily completely, at least one of the reactants. Generally, the nitrogen containing organic base is selected from the group consisting of aromatic and non-aromatic heterocyclics, cyclic and acyclic tertiary amines, and cyclic and acyclic secondary amines having from 3 to 20 carbon atoms. preferably from 3 to about 6 carbon atoms most preferably amines which are liquid at room tem perature. Illustrative examples of these amines are pyridine, imidazole, 2,4-lutidine, trimethylamine, triethylamine, diethylmethylamine, dimethylethylamine, dipropylmethylamine, dimethylpropylamine, methylpropylamine, piperidine, morpholine, quinuclidine, pyrrolidine, dicyclohexylamine, diethylamine, .dipropylamine, .and ethylpropylamin e. (Examples of higher amines include cadaverine, quinoline, isoquinoline, decylamine, hexadecylamine, N-(pchlorobenzhydryl)-piperazine and (di-n-nonylamine).

A cosolvent may be employed to retard freezing and to increase the solubility of the reactants if desired. Effective cosolvents include ethers, amides, alkanes, or

esters. Illustrative examples of ethers are diethylether,

tetrahydrofurane, pyrane, dipropylether, dodecylether and generally monoethers having from 4 to 20 carbon atoms, preferably from 4 to about 6 carbon atoms. Diethers including dioxane, 1,2-dimethoxyethane, diglyme, l,3-dimethoxypropane, and higher ethers can be employed. In general, diethers having from 4 to 20 carbon atoms, preferably 4 to about 6 carbon atoms, can be used. Amides which can be employed are dimethylformamide, N-methylacetamide, N,N- dimethylacetamide, N,N-diethylpropionamide, l-methyl-Z-pyrrolidone and amides in general having from 2 to 19 carbon atoms, preferably from 3 to about 6 carbon atoms. Alkanes which can be employed include those alkanes and isomers thereof from 4 to about 10 carbon atoms, including butane, pentane, hexane, heptane, octane, nonane, decane, and isomers thereof. Esters which can be employed are methylformate, ethylacetate, butylformate, butyl acetate, and in general, esters having from 2 to 18 carbon atoms, preferably from 2 to about 6 carbon atoms. Also useful are nitromethane, acetonitrile, acetone, methylethylketone, chloroform, methylene chloride and dimethylsulfoxide.

After placing the novenamine in the nitrogencontaining organic base and the cosolvent, if included, the temperature of this system is reduced to from about 0C. to about C., preferably from about 20C. to about 40C. This low temperature allows the ensuing reaction between the acylating agent and the novenamine to proceed selectively at the amino position of the novenamide. At this temperature, some of the solvent can be in its solid phase.

When the temperature of the system has been reduced to the desired level, stoichiometric quantities of the acylating agent calculated on the basis of the novenamine present, are added to the system. The acylating agent may go into solution or be in the solid phase at that temperature. The acylating agents employed are the usual acylating derivatives of carboxylic and sulfonic acids which can react with an amino grouping to form an acylated product. Examples of these agents include the following: Halides, anhydrides, mixed anhydrides, chloroformates, nitrophenylesters, and imidazoles. Examples of the halides are fluoride, chloride, bromide, and iodide. Anhydrides and mixed anhydrides include acetic anhdride, benzoic anhydride, and the mixed anhydride formed between isobutyl chloroformate and the N-carbobenzyloxy derivative of tyrosine. Nitrophenyl esters include the nitrophenyl esters of N-carbobenzyloxycarbonyl proline, of l-methoxy-lmethyl-S-carboxychroman, and in general, for such acids where, according to the art, the nitrophenyl esters are known to be advantageously useful. Examples of suitable haloformates include methylchloroformate, cyclododecylchloroformate, and 4- cyclohexylcyclohexylchloroformate. Additionally, other usual acylating derivatives may also be used advantageously. These, in general, include imidazoles, carbodiimides, acylazides and Woodwards Reagent K. When the aforesaid acylating reagents are used under the low-temperature nitrogen-containing organic base solvent conditions of this invention, novenamine is N- acylated in a selective manner.

Operable carboxylic and sulfonic acyl donors can be the standard type usually employed. For example, the carboxylic and sulfonic acyls can be alkyl and aryl, branched or unbranched, cyclic or alicyclic, saturated or unsaturated acyls having from 2 to about 20 carbon atoms, preferably from about to about 16 carbon atoms, and may be unsubstituted or substituted with a variety of radicals such as nitro, hydroxyl, alkoxyl, aeyloxy, halogen, or combinations thereof. Examples include acetic, propionic, palmitic, oleic, 2- methylhexanoic, p-nitrobenzoic, phenoxyacetic, p-toluenesulfonic, acetylsalicylic, m-hexyloxybenzoic, pentaflurorbenzoic, 2-naphthoic, l-adamantoic, chloroacetic, tetradecyloxyformic and the like. A preferred carboxylic grouping is a substituted benzoyl.

After addition of the acylating agents, the temperature of the reaction is allowed to gradually rise to room temperature, a time period which is generally from about 2 to about 20 hours. In general, the slower the temperature rise, the greater the selectivity of the amine acylation. For example, after addition of the acylating agent, the cooling means can be removed from contact with the reaction system and the reaction sys tem allowed to stand overnight, that is, a period of -20 hours, while the system temperature is slowly rising to ambient. When this particular method is employed, N-acylation occurs to the essential exclusion of O-acylation.

After the reaction has reached its desired level of completion, the N-acyl novenamine is isolated in any convenient manner. A preferred method of isolation is to filter the reaction mixture if solids are present and concentrate in vacuo at about C. to about 60C. The residue is partitioned between a 0.01 to about 3N mineral acid such as hydrochloric, sulfuric, perchloric, or phosphoric acid and an immiscible organic solvent such as ethyl acetate, methylene chloride, chloroform, n-butanol or ether. The organic layer is washed successively with water and saturated NaCl solution, dried with MgSO filtered and concentrated. Any solid third phase present is collected by filtration and crystallized from a suitable solvent or solvent pair. The residue of the organic layer is crystallized from the same solvent combination as was the solid third phase, if present. Two crystallizations of the extracted product are usually required to obtain material of a purity level equivalent to that obtained from a single crystallization of the product which was present as a third phase above. Suitable crystallization solvents are combinations of lower alcohols or ketones of up to about 5 carbon atoms and water or a halogenated hydrocarbon such as methylene chloride and a hydrocarbon such as hexane, cyclohexane, ligroin or toluene.

The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.

EXAMPLE 1 N-(4-Nitro-3-n-pentyloxybenzoyl) Novenamine Novenamine (13.5 g.) is dissolved in pyridine (250 ml) and the solution flushed with nitrogen and cooled to the point where solid begins to form on the wall of the flask (ca 30C.). 4Nitro-3-n-pentyloxybenzoyl chloride 2' g.) is added in one batch. The mixture is stirred for l6 hr. during which time the temperature rises to 25C. The solvent is removed on a rotary vacuum evaporator (60/l8 mm) and the residue partitioned between ethyl acetate and l N hydrochloric acid. The organic layer is washed with water, dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue is taken up in hot ethanol and cooled. The solution deposits 12.0 g. yellow solid, m.p. ll77.

Anal. Calcd. for C H N O C, 56.44; H, 5.65;

.37. Found: C, 55.83; H, 5.79;

EXAMPLE 2 N-(3-n-Nonyloxybenzoyl) Novenamine Anal. Calcd. for C H N O C, 62.67; H, 6.91;

N, 4.18. Found: C, 62.43; H, 7.07;

EXAMPLE 3 N-(3Benzyl-4-Hydroxybenzoyl) Novenamine Novenamine (8.4 g.) is dissolved in ml. pyridine and 100 ml. tetrahydrofuran. The solution is flushed with nitrogen and cooled to 35. 3-Benzyl-4- benzyloxybenzoyl chloride (from 6.4 g. of the acid and an excess of thionyl chloride) is added in one batch. The temperature rises to 28 briefly and then returns to 35. Stirring is continued for 64 hr., during which time the temperature reached 25. The solution is concentrated on a rotary evaporator and the residue partitioned between ethyl acetate and l N HCl. The organic layer is washed with water, dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator. This is taken up in ethyl acetate and filtered with suction over 400 g. silica gel. The first 650 ml. filtrate is concentrated to give 7.5 g. yellow solid. This has an R, using 10:1 ethyl acetate: methanol on a silica gel thin layer plate of 0.64. It is analyzed without further purification to give C, 66.89 and H, 5.75 (calculated for C H N O is C, 66.29 and H, 5.56).

This material (3.6 g.) is hydrogenated at 38 psi hydrogen in ml. methanol with 1.5 g. 10% Pd/C on a Parr hydrogenation apparatus. The solution is filtered and concentrated on a rotary evaporator. The residue is dissolved in hot ethyl acetate, filtered and treated -Cont1nued Melting Point "C (Accompanied by R decomposition) 4-hydroxy-3-n-(3-methylbutyloxy)- benzoyl l74-5 4-hydroxy-3-( 3-oxobutyl )-benzoyl l435 3 (l-oxo-n-pentyU-benzoyl l39 3 (l-hydroxy-n-pentyl)-benzoyl 197 benzoyl 245 4-acetoxy-3-allylbenzoyl 120-22 3-allyl-4-hydroxybenzoyl l68-70 4'acetoxy-3-n-propylbenzoyl 220-4 4-hydroxy-3-n-pentylbenzoyl 148-5 1 4hydroxy-3-n-propylbenzoyl l349 4-acetoxy-3-n-hexylbenzoyl l22 3-n-hexyl-4-hydroxybenzoyl l38 1 40 3-n-heptyl-4-hydroxybenzoyl l38-42 4-hydroxybenzoyl 2568 isobutyryl l44-8 n-heptanoyl l46-8 n-nonanoyl l73--8 n-dodecanoyl l48-52 n-tetradecanoyl l247 Z-furanoyl l22-30 cinnamoyl 228-31" 4hydroxycinnamoyl l37-43 4-m ethoxycinnamoyl 231-5" 4-allyloxycinnamoyl 2057 3-(4-n-propyloxyphenyl)-propionoyl 80 (dec 3-(4-n-pentyloxyphenyl)-propionoyl 4-hydroxy-3-methoxycinnamoyl l65-7 4-acetoxy-3-methoxycinnamoyl l658 3.4-dimethoxycinnamoyl 2647 3-phenylpropionoyl 2204 3-aminobenzoyl 2589 4-amino-3-nbutoxybenzoyl l66-8 3-amino-4-methoxybenzoyl 2678 4-amino-3-hyd roxybenzoyl 189-9 2 4-amino-3-n-propyloxybenzoyl 135-7 4-amino-3-n'pentyloxybenzoyl 138-4 1 4-amino-3-( 3-methylbutoxy )-benzoyl gal-40 4-amino-3-( l-methyl-l-n-butoxy)-benzoyl 4-amino-3-(2-ethoxyethoxy)-henzoyl l59-62 4-amino-3-n-octyloxybenzoyl l23-6" 3Tamino4-n-butoxybenzoyl l 5660 4-amino-3-methylbenzoyl l97-8 3-amino-4-methylbenzoyl l 87-94 l l-bromodecanoyl l 3 l5 N-methylanthranoyl l50'-55 anthranoyl 2 l 2l 7 cyclohexylphenylacetyl l 349 The novenamine N-acylates selectively prepared by the process of this invention are useful in the same manner as the uses of novenamine and N-acylates of novenamine described in US. Pat. No. 3,652,536 at Column 7, lines 25--37. They are particularly useful as a disinfectant on various dental and medical equipment contaminated with S. aureus.

I claim:

1. A process for preparing N-acylated novenamine having anti-bacterial activity which comprises contacting novenamine with an acylating agent consisting of a derivative of the desired carboxylic or sulfonic acid in a nitrogen-containing organic base solvent at a temperature of from about C. to about 0C. and allowing the reaction system to come to ambient temperature.

2. A process in accordance with claim 1 wherein the temperature is from about -40 to about -20C.

3. A process in accordance with claim 2 wherein the solvent is pyridine.

4. A process in accordance with claim 1 wherein said carboxylic or sulfonic acid has two to about 20 carbon atoms, inclusive. 

1. A PROCESS FOR PREPARING N-ACYLATED MOVEAMINE HAVING ANTI-BACTERIAL ACTIVITY WHICH COMPRISES CONTACTING MOVENAMINE WITH AN ACYLATING AGENT CONSISTING OF A DERIVATIVE OF THE DESIRED CARBOXYLIC OR SULFONIC ACID IN A NITROGEN-CONTAINING ORGANIC BASE SOLVENT AT A TEMPERATURE OF FROM ABOUT -80*C. TO ABOUT 0*C. AND ALLOWING THE REACTION SYSTEM TO COME TO AMBIENT TEMPERATURE.
 2. A process in accordance with claim 1 wherein the temperature is from about -40* to about -20*C.
 3. A process in accordance with claim 2 wherein the solvent is pyridine.
 4. A process in accordance with claim 1 wherein said carboxylic or sulfonic acid has two to about 20 carbon atoms, inclusive. 